These new flavone compounds are group 4 phosphodiesterase (PDE4) inhibitors and, as a result, possess highly advantageous therapeutic applications.
In effect, the functions of most organic tissues are modulated by endogenous substances (hormones, neurotransmitters, autacoids) or exogenous substances. For some of these substances, the biological effect is relayed at intracellular level by enzyme effectors such as adenylate cyclase or guanylate cyclase. The stimulation of these enzymes, which are responsible for the synthesis of cyclic nucleotides such as cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP), brings about a rise in the intracellular level of these second messengers involved in the regulation of a large number of biological functions (E. W. Sutherland and T. W. Rall, Pharmacol. Rev., 12, (1960), 265).
The degradation of cyclic nucleotides is effected by a family of enzymes called phosphodiesterases (PDE), currently classified in 7 groups. The recognition of different isoforms within each of these groups, and of the tissue- or cell-specific distribution of certain isoforms, has stimulated the search for increasingly specific inhibitors of one or other type of isoenzyme (J. A. Beavo, Physiological Rev., 75 (4), (1995), 725-749). Among the different PDE families, PDE4 has been identified in a very large number of tissues or cells, such as brain, heart, vascular endothelium, vascular and tracheobronchial smooth muscle and hematopoietic cells. Inhibition of the phosphodiesterases slows down the hydrolysis of the cyclic nucleotides and brings about an increase in the cAMP and/or cGMP content.
PDE4 inhibitors, which are responsible for an increase in cAMP levels, possess anti-inflammatory activities and relaxant effects on tracheobronchial smooth muscle, which accounts for their therapeutic value in the field of respiratory pathology or pathologies associated with an inflammatory process (M. N. Palfreyman, Drugs of the Future, 20 (8), (1995), 793-804; J. P. Barnes, Eur. Respir. J., 8, (1995), 457-462; S. B. Christensen and T. J. Torphy, Annual Reports in Medicinal Chemistry, 29, (1994), 185-194, Academic Press).